美国全国儿童医院的研究者公布了一份基因治疗方案，改善鼠实验中的遗传性血液紊乱-β-地中海贫血病症，基因改善是使用鼠的未受精卵制造胚胎干细胞系。这些干细胞系没有遗传疾病基因，可用于小鼠的移植治疗。

该发现发布在《临床研究期刊》(Journal of Clinical Investigation)上，对于治疗常染色体显性遗传疾病，如β-地中海贫血、结节性硬化症或亨廷顿氏病的治疗方案提供了新的希望。

胚胎干细胞可发展成各种类型的细胞，可用于许多疾病的治疗。未受精卵可被培养成胚胎干细胞，即孤雌胚胎干细胞。全国儿童医院研究所分子与人类遗传学中心的首席研究员，麦克考林博士认为：孤雌胚胎干细胞可以分化为各种组织类型，正如干细胞是来自于受精的胚胎。在此之前，该研究组表示来自于孤雌胚胎细胞的血液细胞可在小鼠体内提供健康、长期的血液置换。

麦克考林博士说，孤雌干细胞的优点不仅是不需要受精，并且接受者的免疫系统不会将其作为异物，减少排斥反应的问题。此外，由于孤雌胚胎干细胞是来自于生殖细胞-包含了单一的基因信息，他们不会有某种畸变基因的存在。

麦克考林博士与来自宾夕法尼亚大学、北卡罗来纳州大学和明尼苏达大学的同事们共同验证了孤雌胚胎干细胞是否可对患有中间型地中海贫血的小鼠进行组织修复。中间型地中海贫血是一种遗传性血液紊乱，身体缺少足够的正常血红蛋白，导致血红细胞遭到破坏及贫血。

该种方法是源自于全国儿童医院的斯格德博士进行的研究，胚胎干细胞来自于患有疾病的雌鼠的未受精卵，并且确认这些干细胞系包含的仅是健康的血红蛋白基因。这些"基因清洁"的胚胎干细胞系被转换为细胞，该细胞可移植入携带疾病的小鼠。移植五周后的血液样本显示获取的细胞出现在接受者的血液内。他们的血液细胞被纠正为与正常小鼠的相类似，红细胞计数、红细胞比积以及血红蛋白恢复到正常水平。

总而言之，斯格德博士说，我们观察到试验中地中海贫血病症的持续改善，麦克考林博士说，我们的发现表明，利用生殖细胞产生胚胎干细胞，可解决的遗传疾病的问题，该方法与无需基因组工程的典型基因治疗方法不同。

英文摘要：

J Clin Invest. doi:10.1172/JCI45377.

Gene therapy by allele selection in a mouse model of beta-thalassemia
Sigrid Eckardt1, N. Adrian Leu2, Ashley Yanchik2, Seigo Hatada3, Michael Kyba4 and K. John McLaughlin1,5

1Center for Molecular and Human Genetics, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA.
2University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
3Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
4Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
5Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

To be of therapeutic use, autologous stem cells derived from patients with inherited genetic disorders require genetic modification via gene repair or insertion. Here, we present proof of principle that, for diseases associated with dominant alleles (gain-of-function or haploinsufficient loss-of-function), disease allele–free ES cells can be derived from afflicted individuals without genome manipulation. This approach capitalizes on the derivation of uniparental cells, such as parthenogenetic (PG) ES cell lines from disease allele–free gametes. Diploid mammalian uniparental embryos with only maternally (oocyte-) or paternally (sperm-)derived genomes fail early in development due to the nonequivalence of parental genomes caused by genomic imprinting. However, these uniparental embryos develop to the blastocyst stage, allowing the derivation of ES cell lines. Using a mouse model for dominant beta-thalassemia, we developed disease allele–free PG ES cell lines from the oocytes of affected animals. Phenotype correction was obtained in donor-genotype recipients after transplantation of in vitro hematopoietic ES cell derivatives. This genetic correction strategy without gene targeting is potentially applicable to any dominant disease. It could also be the sole approach for larger or more complex mutations that cannot be corrected by homologous recombination.